Bacteria-mucin interactions – Shaping intestinal epithelial responses in health and disease
|Bacteria-mucin interactions – Shaping intestinal epithelial responses in health and disease
|European Research Council - Starting Grant (ERC-StG)
The intestinal microbiota consists of beneficial commensal bacteria and pathobionts that cause inflammation. The intestinal mucus layer dictates how specific members of the microbiota affect health and disease. The mucus layer consists of soluble mucins and epithelial transmembrane (TM) mucins that regulate host responses. The molecular mechanisms as to how the intestinal microbiota affect the functions of TM mucins is largely unknown. My recent work shows that TM mucin MUC1 is a key receptor for Salmonella invasion into polarized epithelial cells. We also discovered that MUC13 is a central regulator of epithelial barrier formation. I hypothesize that bacteria-mucin interactions shape epithelial responses by stimulating healthy barrier formation, driving inflammation or mediating bacterial invasion. My aim is to unravel molecular mechanisms via which distinct bacterial species regulate the functions of TM mucins MUC1 and MUC13 in the intestine. The key objectives of Bac2MUC are to: 1. Identify commensal and pathogenic bacteria that target TM mucins 2. Elucidate TM mucin signaling pathways activated by commensal and pathogenic bacteria 3. Determine the function of TM mucins during inflammation and invasion 4. Utilize bacteria-TM mucin interactions to unravel healthy epithelial barrier regulation I will use an innovative large-scale screening platform to identify novel bacteria-mucin interactions. TM mucin signaling pathways during bacterial interaction will be characterized by sortase technology. Cutting-edge technologies such as CRISPR/Cas9 genome editing and advanced microscopy will be applied in established bacterial infection assays with intestinal cell lines and organoids. Bac2MUC is an ambitious and ground-breaking project that will address, for the first time, the complex interplay between intestinal bacteria and TM mucins. This project will contribute to clinical strategies that prevent intestinal inflammation and improve mucosal barrier function.